Project Summary One of every 20 Americans develops colorectal cancer (CRC) and, once diagnosed, more than one-third will not survive 5 years. Although screening is available, stool assays such as fecal immunochemical test (FIT) have true positive rates ranging between 64-68% and false positive rate ranging between 5-10%. Moreover, other approaches such as colonoscopy are invasive and expensive and have low rates of patient adherence. There is clearly a need for improved non-invasive methods to screen individuals or subsequent colonoscopy. The current proposal describes using an innovative source of CRC-related biomarkers: the gut microbiome. This collection of bacteria inhabits the gastrointestinal tract and has largely been ignored in previous studies of the etiology and detection of CRC in humans. The long-term goal of this research is to develop biomarkers that improve the detection of CRC and to understand the mechanisms behind the biological changes that increase the risk of developing CRC. The objective of this proposal is to assess the use of microbiome-based fecal biomarkers of CRC. The central hypothesis is that development of colonic adenomas and carcinomas is in part mediated by the gut microbiome and that changes to the microbiome can be used to identify changes in health. Animal studies from have demonstrated that changes in the microbiome can lead to chronic local and systemic inflammation, which promotes the development of CRC. Through a recent collaboration with the University of Michigan members of the Early Detection Research Network Great Lakes New England Clinical Validation Center it was shown that the abundance of bacterial populations within intact feces could significantly improve the ability to detect CRC. The current proposal seeks to demonstrate that combining microbiome-based analyses with standard stool-based analyses will improve CRC detection. Three specific aims are proposed: (i) quantify the sensitivity and specificity of a combined FIT and microbiome model to improve the sensitivity and specificity of detecting SRN, (ii) assess the ability of residual FIT material to serve as a proxy for a whole fecal sample in detecting SRN, and (iii) measure the association between patient characteristics and model performance. The proposed research will yield a significant contribution because for the first time there will be a validated set of biomarkers for CRC that are based on the microbiome that approach the predictive value of colonoscopies for a fraction of the cost. The proposed research is innovative because of its scope, target population and ability to link microbiome composition with a physical sample, access to patient clinical data, and potential opportunities to incorporate data from parallel biomarker validation studies that have used the same samples. Successful completion of these aims will yield a significant translational step in the detection of colonic adenoma with a very real opportunity to develop a robust panel of microbial biomarkers that complement existing technologies.